The broad long-term goal of this application is to uncover the mechanism of retinal ganglion cell (RGC) degeneration in glaucoma so as to be able to design rational therapeutic interventions based on neuroprotection. Based on recent data showing that glaucoma animal models develop aggregates of ?-synuclein in the retina and optic nerve similar to the aggregates composed of a-synuclein in Parkinson's disease and animal models, it appears likely the glaucoma and Parkinson's disease share many pathogenic mechanisms. The proposed studies aim to understand the nature and significance of the ?-synuclein aggregates in glaucoma animal models. There are two processes that appear to correlate with the development of the ?-synuclein aggregates in mice that undergo glaucoma-like changes. First, despite ?-synuclein being expressed normally only in RGC, in glaucoma animal models there are a newly-identified subset of astrocytes within the optic nerve head that contain ?-synuclein aggregates and upregulate a pathway that is linked to phagocytosis. Second, the ?-synuclein aggregates are found associated with a lipid organelle, the lipid droplet, and there is a large increase in these lipid droplets in the glaucoma animal models. The proposed experiment aim to determine whether there is a cause and effect relationship between the ?-synuclein aggregates and these two associated phenomena. Independently, they will test whether these associated phenomena have any relevance to glaucoma progression. Finally, since animal models do not always reflect changes in human diseases, key findings made in these animal models regarding ?-synuclein aggregates, astrocyte phagocytosis, and lipid droplet formation, will be examined in the retinas and optic nerves of verified glaucoma patients. It is likely that the proposed studies will shed much light onto how synucleins function in health and disease. Importantly, in identifying a key pathological mechanism in glaucoma that is so similar to those seen in other common neurodegenerative disorders, the proposed studies may revolutionize how glaucoma is studied and, in the future, treated. PUBLIC HEALTH RELEVANCE: It is likely that the proposed studies on the role of ?-synuclein in glaucoma will yield much new information about how synucleins function in health and disease. Most importantly, the proposed studies will revolutionize how glaucoma is studied and treated, and likely will be a large step forward in bringing neuroprotective therapies to those afflicted by this second most common of all neurodegenerative disorders, glaucoma.